Abstract
Macrophages are highly plastic immune cells that adopt diverse functional states in response to the local microenvironment. The traditional M1/M2 polarization model that has long been used to describe macrophage activation is insufficient to capture the full spectrum of macrophage diversity observed in vivo. Advances in single-cell RNA sequencing (scRNA-seq) have revealed that macrophages exist in a continuum of transcriptional states formed by tissue-specific and disorder-specific cues. This insight has led to the recognition of disorder-specific macrophages, defined as macrophage subpopulations that emerge in response to pathological stimuli and play unique roles in disease progression. These macrophages exhibit distinct transcriptional signatures, epigenetic modifications, and functional properties shaped by their ontogeny and microenvironmental signals, arising from the reprogramming of resident macrophages or the differentiation of bone marrow-derived progenitors. Notable examples include macrophages in chronic infections (e.g., tuberculosis), immunosuppressive tumor-associated macrophages, lipid-associated macrophages in obesity, and disease-associated microglia in neurodegeneration. These subsets exhibit unique regulatory mechanisms, including enhancer remodeling driven by histone H3 lysine 27 acetylation in non-alcoholic steatohepatitis, CCAAT enhancer binding protein α-mediated differentiation in obesity, and Jmjd3-IRF4 axis control in allergic inflammation. Additionally, their function and fate are strongly influenced by their subtissular niche, as evidenced by crown-like structures in adipose tissue, tumor microenvironments, fibrotic lesions, and granulomas, where distinct microenvironmental cues shape macrophage behavior. Furthermore, interindividual heterogeneity in macrophage function, driven by genetic polymorphisms, is increasingly recognized, highlighting the role of host genetic background in disease susceptibility and macrophage-driven pathology. Here, we review the conceptual evolution of the disorder-specific macrophage, tracing its origins from the limited M1/M2 model to its refinement through scRNA-seq-based classification. We summarize the ontogeny, transcriptional regulation, and spatial heterogeneity of these macrophages across various disorders, emphasizing how the subtissular niche dictates functional specialization. Finally, we discuss potential therapeutic strategies targeting disorder-specific macrophage subsets, highlighting the need for integrative multi-omics approaches to refine their classification and functional characterization. Understanding the regulatory networks that govern disorder-specific macrophages will advance our knowledge of macrophage biology while facilitating the development of precision medicine for immune-related disorders.